Malignant melanoma is an immunogenic, highly aggressive and most lethal form of skin cancer. It is the most common cancer in the 17-34 years age group but affects people of all ages, and therefore has a significant socioeconomic impact for patients and their families Rates of melanoma have been rising by 5% per year, faster than any other cancer in the UK [1]. Although diagnosed skin lesions can be initially excised by surgical intervention, skin and distal metastases unfortunately occur in 20% of patients originally treated with local disease. Patients with lymph node and other distal metastases have dismal prognosis, and this is partly due to lack of effective treatments for this cohort.
Melanoma has presented major challenges to numerous targeted therapy efforts and therefore effective treatments are urgently needed for patients with this disease. The recent approval of the monoclonal antibody ipilimumab (targeting the CTLA4 blockade to enhance T cell activation) for the treatment of melanoma lends merit to the notion that activating immune responses with antibodies may have therapeutic significance and has renewed interest in the field of antibody therapies for the treatment of challenging tumours such as melanoma [2-4]. Despite the partial success and promise of various immunotherapeutic strategies, including antibodies, there are presently no promising antibody therapies that directly target antigens on the surface of melanoma cells.
Therapeutic antibodies now complement conventional treatments for a number of malignant diseases, but almost all agents currently developed rely on only one of the nine human antibody classes, namely IgG1, the most abundant antibody class in the blood [5]. The human immune system naturally deploys nine antibody classes and subclasses (IgM, IgD, IgG1-4, IgA1, IgA2 and IgE) to perform immune surveillance and to mediate destruction of pathogens in different anatomical compartments. Yet only IgG (most often IgG1) has been applied in immunotherapy of cancers.
One reason may be that IgG antibodies (particularly IgG1), constitute the largest fraction of circulating antibodies in human blood. The choice of antibody class is also based on pioneering work in the late 1980s, comparing a panel of chimaeric antibodies of the same specificity, each with Fc regions belonging to one of the nine antibody classes and subclasses [6]. Antibodies were evaluated for their ability to bind complement and their potency to mediate haemolysis and cytotoxicity of antigen-expressing target cells in the presence of complement. IgG1 in combination with human peripheral blood mononuclear cells (PBMC) was the most effective IgG subclass in complement-dependent cell killing in vitro, while the IgA and IgE antibodies were completely inert.
Subsequent clinical trials with antibodies recognising the B cell marker CD20 supported the inference that IgG1 would be the subclass best suited for immunotherapy of patients with B cell malignancies such as non-Hodgkin's lymphoma [7]. Since those studies, comparisons of anti-tumour effects by different antibody classes have been confined to IgG and IgM in both murine models and patients with lymphoid malignancies, while IgA has been shown to mediate ADCC in vitro and in vivo in mouse models of lymphoma [8-12]. IgA and IgE antibodies, on the other hand, have never been tested in cancer patients.
Complement-mediated tumour cell death is now known to be only one of several mechanisms by which antibodies may mediate tumour growth restriction [13]. Known mechanisms include engaging immune effector molecules through their Fc regions to induce immune cell mediated destruction of targeted cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP). Antibodies can also act directly on tumour cells to inhibit growth signalling pathways, induce apoptosis, restrict proliferation and cell differentiation of tumour cells, or block tumour cell adhesion and migration. Some antibodies are developed to recognise targets associated with tumour-associated vasculature in order to starve tumours of vital nutrients delivered through blood supply, while others attack immune regulatory targets (e.g. CTLA-4 and PD-1R) to enhance T cell activation and overcome immunosuppressive elements of the immune response [14, 15, 3]. Extensive efforts have also focused on designing antibody conjugates to deliver toxic payloads in the form of drug-activating enzymes, cytokines or radionuclides to tumours [16]. Multiple antibody engineering approaches are also being devised to improve validated therapeutics, such as trastuzumab, with the principal aims to optimise antigen specificity/affinity and effector functions of IgG antibodies [17].
Accordingly, there is still a need for improved therapeutic antibodies, particularly for the treatment of neoplastic diseases such as skin cancer. In particular, there is a need for antibodies having improved effector functions compared to IgG antibodies, which may lead to an improved clinical outcome in the treatment of cancer, especially skin cancer.